2. Academic Validation
  3. Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

  • Nat Commun. 2023 Feb 9;14(1):731. doi: 10.1038/s41467-023-36409-z.
Hanlin Lu 1,  Peidong Yuan 1,  Xiaoping Ma 1 2,  Xiuxin Jiang 3,  Shaozhuang Liu 3,  Chang Ma 1,  Sjaak Philipsen 4,  Qunye Zhang 1,  Jianmin Yang 1,  Feng Xu 5,  Cheng Zhang 1,  Yun Zhang 1,  Wencheng Zhang 6
Affiliations

Affiliations

  • 1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, China.
  • 2 Department of Obstetrics and Gynecology, LiaoCheng People's Hospital, LiaoCheng, China.
  • 3 Department of Bariatric and Metabolic Surgery, General Surgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, China.
  • 4 Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
  • 5 Department of Emergency Medicine, Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
  • 6 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, China. [email protected].
PMID: 36759621 DOI: 10.1038/s41467-023-36409-z
Abstract

Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2/KDR/Flk-1 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating Enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment.

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